Diabetes mellitus, often referred to simply as diabetes, encompasses a variety of conditions that involve disordered metabolism, the typical feature of which is abnormally high blood sugar levels (hyperglycemia). Blood sugar levels are controlled by a complex network of chemicals and hormones in the human body, including the hormone, insulin, produced by the beta cells of the pancreas. The abnormally high level of blood sugar seen in a diabetic patient is caused by defects in either insulin secretion or insulin action, attributable to a combination of hereditary, acquired, and environmental factors. Majority of diabetes are either type 1 diabetes, previously known as childhood-onset diabetes and insulin-dependent diabetes, or type 2 diabetes, previously known as adult-onset diabetes and insulin-independent diabetes.
Type 1 diabetes is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas, resulting in a deficiency of insulin production. The principal treatment for this type of diabetes is therefore delivery of artificial insulin, usually via injection. Type 2 diabetes is more common than type 1 diabetes with over 90% of affected people having type 2 diabetes. The latter is closely associated with modernization characterized by obesity and insulin resistance (reduced insulin sensitivity) although diminished insulin production is needed for development of overt hyperglycemia. Both twin and family studies support a strong genetic component for type 2 diabetes. Recent genetic implicate multiple common genetic variants in the development of type 2 diabetes although these factors only explained a small percentage of the variance of the genetic risk of type 2 diabetes. Furthermore, there is strong evidence showing inter-ethnic differences in distribution and frequency of genetic or sequence variants for diabetes such that many of these variants discovered in Caucasian populations may not be applicable to Asian population due to different patterns of linkage disequilibrium and recombination hotspots.
Various factors are known to be indicative of a person's risk to develop type 2 diabetes, most of them strongly influenced by the person's lifestyle, age, ethnic background, and family history. The presence of at least one, often more than one, of these risk factors, such as a body mass index (BMI) in the range of obesity (especially central obesity due to accumulation of excess visceral fat as indicated by large waist circumference), elevated blood glucose or insulin level (especially elevated fasting or post prandial blood glucose or insulin level), and reduced sensitivity to insulin, predisposes a person to the high likelihood of developing type 2 diabetes, if no corrective measure is taken.
As people's living standards continue to improve globally, the number of individuals suffering from diabetes is also rapidly increasing. The World Health Organization (WHO) estimates that by 2030 the number of people living with diabetes will exceed 350 million worldwide. Due to the rising incidence of diabetes, its chronic nature without an ultimate cure, and serious health implications associated with its complications, including but not limited to cardiovascular disease, kidney failure, cancer, blindness, leg amputation, there exists an urgent need for new and effective means to assess or predict the risk of individuals who might later develop diabetic conditions, so that prophylactic measures can be taken to prevent or delay the onset of diabetes in these individuals or to reduce severity of the pertinent symptoms/risks associated with diabetes.
It is now clear that diabetes increases risk of all site cancers by 30% except for prostatic cancer. In the US, Asian subjects are known to have higher cancer risk than non-Asian subjects, in particular, liver and gastric cancers. These predilections for cancer development may be related to the interaction between external carcinogens (e.g., tobacco, alcohol, food, and low grade infections, such as hepatitis B infection) and abnormal metabolic environment due to high blood glucose, high blood lipid, and kidney failure. Besides, subjects with chronic kidney disease are at extremely high risk for cardiovascular disease due to changes in metabolic milieu including oxidative stress, low grade inflammation, vascular calcification, and anemia, which will increase risk of vascular damage. Thus, a person with diabetes or at risk for diabetes has very high risk for these co-morbidities including but not limited to cancer, cardiovascular and kidney disease, which are closely linked.
There are also clinical and experimental data showing that good glycemic control and use of certain drugs such as statins (which inhibit the HMG coA reductase), blockers of renin angiotensin system, and blood glucose lowering drugs including but not limited to insulin, sulphonylureas, metformin and glitazones, may not only reduce the risk of cardiovascular and renal disease but also cancer. These preventive measures are especially important in high risk subjects such as those who have additional risk factors for cancer and cardiovascular disease, e.g., positive family history of diabetes (suggesting the possibility of harboring other genetic factors yet to be identified), chronic hepatitis B infection, chronic kidney disease, and low BMI (reflecting poor pancreatic beta cell functions). In these high risk subjects, detection of genetic risk factors before severe metabolic decompensation will help clinicians to intensify treatment in order to prevent metabolic deterioration and optimize metabolic control to reduce risk of cancer, cardiovascular and renal disease.
Because of the enormous social and economical impact the above discussed diseases incurs globally, there exist clear and immediate needs to develop new and effective means for accurate diagnosis of these diseases or early assessment a patient's risk of developing these diseases in the future, such that early intervention may be performed to minimize the harmful effects associated with these diseases and/or the risk of developing the diseases. The present invention fulfills this and other related needs.